The long-term goal of the proposed experiments is repair of neocortical projection neuron circuitry. This work aims toward the ultimate goal of repair by manipulation of endogenous neural progenitors in situ. This could lead to therapies for degenerative, developmental, or acquired diseases of cortex and its output circuitry (e.g. corticospinal). In neocortex, the effectiveness of such future therapies could depend critically on whether endogenous progenitors can be precisely induced to form the correct, subtype-specific neurons; differentiate and integrate appropriately; and re-form long-distance projections and complex functional connections. At the time of submission for the initial period of this grant, we had recently published (Magavi, Nature, 2000; Scharff, Neuron, 2000) the field's first demonstrations of induction of neurogenesis, the birth of new neurons, from endogenous progenitors in the adult brain. We chose corticothalamic projection neurons (CThPN) and their development for focused study in mice toward induction of neurogenesis because they are a prototypical population of long-distance cortical projection neurons, and because of their location closest to the available pool of caudal cortical SVZ progenitors. We hypothesized (now with substantial data during development and pilot adult data) that there exist partially fate-specified neocortical progenitors competent to differentiate into corticofugal neurons, including CThPN (Molyneaux, Neuron, 2005; Arlotta, Neuron, 2005; Molyneaux, Nat Rev NSci, 2007; Lai, Neuron, 2008; Joshi, Neuron, 2008; Azim, 2008). A next logical step toward future therapeutic manipulation of endogenous progenitors and induction of neurogenesis will be directed differentiation of specific neuron populations by manipulating combinatorial molecular-genetic controls. Though we have made considerable progress identifying cellular and molecular conditions that enable cortical neurogenesis and partial repair of adult cortical circuitry, many questions still remain to be investigated. These questions form the basis of the proposed research. Building on recent results, proposed experiments (Aim 1) functionally investigate FOG-2, a newly identified transcriptional regulator critical for CThPN development, using loss- and gain-of-function in vivo; (Aim 2) investigate two new candidate combinatorial molecular-genetic controls over CThPN birth and development; (Aim 3) investigate whether partially fate- restricted neural progenitors, recently identified during development, exist in the adult mouse neocortex, with potentially enhanced competence to generate corticofugal neurons; and (Aim 4) induce CThPN neurogenesis from (potentially) partially fate-restricted progenitors in the adult mouse forebrain via manipulation of critical molecular-genetic controls over CThPN development. Together, these experiments will significantly advance our ability to induce type-specific neurogenesis and ultimately direct functional circuit repair of the adult CNS.